Sex-Specific Neurodevelopmental Outcomes Among Offspring of Mothers With SARS-CoV-2 Infection During Pregnancy

Key Points Question Is in utero exposure to maternal SARS-CoV-2 infection associated with greater rates of neurodevelopmental disorder diagnoses in male or female offspring, compared with controls with no such exposure? Findings This cohort study of 18 355 infants delivered after February 2020 found that male but not female offspring born to mothers with a positive SARS-CoV-2 polymerase chain reaction test result during pregnancy were more likely to receive a neurodevelopmental diagnosis in the first 12 months after delivery, even after accounting for preterm delivery. Meaning These findings suggest that male offspring exposed to SARS-CoV-2 in utero may be at increased risk for neurodevelopmental disorders.


eMethods. Analysis
In sensitivity analyses, we repeated the primary outcome analyses confining the analyses to only those offspring who had a 12-month visit within our hospital system (with a 60-day window before or after the 12-month mark), to understand whether associations could be confounded by differential in-person followup among exposed or unexposed offspring. We also performed a sensitivity analysis including only offspring with an 18-month visit within our hospital system, again with a 60-day window before and after the 18-month mark.
To examine the robustness of multiple regression results by applying an alternative approach to potential confounding variables, we also applied exact matching to match each SARS-CoV-2-exposed offspring with at least one SARS-CoV-2-unexposed offspring on the same features used in regression models (i.e., race, ethnicity, maternal age, insurance type, hospital type, and preterm delivery). Where regression models estimate an average treatment effect, the matched cohort provides an approximation of the average treatment (i.e., exposure) effect among exposed individuals. We used the R matchit (v4.4.0) package for these analyses, allowing as many exact matches among controls as available -i.e., 1:n matching -to maximize precision in estimates of effect. Allowing more than 1 match for each exposed case where available (rather than 1:1) allows greater power to detect association given the larger available pool of controls. To quantify the effect of misclassification of exposure on estimates of association 30 , we used the R episensr package (v1.1.0).

eResults. Sensitivity Analyses
In sensitivity analyses, we also fit logistic regression models with the cohort restricted to offspring with at least one follow-up visit within our hospital system at 12 months (Supplemental Table 4; n=383 SARS-CoV-2 exposed and 6635 unexposed, including 26/383 (6.8%) and 309/6635 (4.7%) with a neurodevelopmental diagnosis, respectively). These models supported the robustness of the primary analysis, yielding results of similar magnitude to those of the full cohort: adjusted OR was 1.76 (1.00-2.94), p=.04 for males, 0.82 (0.36-1.66, p=.61) for females, and 1.31 (0.83-1.99, p=.22) for both sexes combined (Supplemental Figures 2A, B, and C).
To further examine the robustness of these associations, we used exact matching on the same features as regression -maternal age, race, ethnicity, insurance status; hospital type; and preterm status-to examine the association between offspring SARS-CoV-2 exposure and neurodevelopmental diagnosis. Among males, matching 397 COVID-exposed offspring with 6055 COVID-unexposed offspring, OR for any neurodevelopmental disorder at 12 months was 1.88 (95% CI 1.05-3.37; p=.04), and for female offspring matching 382 COVID-exposed to 5803 COVID-unexposed, OR was 1.22 (0.51-2.47, p=.6). For the cohort as a whole, matching 779 COVID-exposed offspring with 11858 COVID-unexposed offspring, OR was 1.56 (95% CI 0.95-2.41; p=.06). Applying coarsened exact matching rather than exact matching did not was consistent with initial results; see Supplemental Table 5. These sensitivity analyses demonstrated consistent direction of effect across both matched analyses and logistic regression models.
We also tested for the presence of secular trends in diagnosis of neurodevelopmental disorders by comparing 12-month outcomes among children born during the pandemic to two pre-pandemic cohorts. These analyses were all conducted based on birth during versus pre-pandemic, and did not take into account maternal SARS-CoV-2 status. Compared to 2018 (Supplemental Table 7, all children followed up pre-pandemic), a modest but not statistically significant increase in rates of neurodevelopmental diagnoses (Supplemental Table 8) was identified among males (adjusted OR 1.11, 95% CI 0.89-1.39), p=.37) as well as females (adjusted OR 1.28, 95% CI 0.99-1.66), p=.06); analyses pooling both sexes also failed to meet statistical significance adjusted OR=1.18, 95% CI 0.99- 1.39,p=.06;Supplemental Figures 5A,B,and C). Compared to the 2019 pre-pandemic cohort (Supplemental Table 9), all children born pre-pandemic but all with 12-month follow-up intra-pandemic), for children born during the pandemic, adjusted OR for neurodevelopmental diagnoses at 12 months among male offspring was 1.24, 95% CI 0.99-1.56, p=.06; for females, 1.26, 95% CI 0.98-1.62, p=.08; analyses pooling both sexes, 1.24, 95% CI 1.05-1.47, p=.01 (Supplemental Figures 6A, B,